Acyl derivatives of erythromycin oxime

ABSTRACT

MONO-AND BIS-CARBOXYLIC ACID ACYLATES OF ERYTHROMYCIN OXIME, USEFUL AS ANTIBIOTICS.

United States Patent 3,574,185 ACYL DERIVATIVES 0F ERYTHROMYCIN OXIME Zrinka Tamburasev, Gabrijela S. Vazdar-Kobrehel, and Slobodan Djokic, Zagreb, Yugoslavia, assignors to PLIVA Pharmaceutical and Chemical Works, Zagreb, Yugoslavia No Drawing. Filed July 16, 1968, Ser. No. 745,104 Claims priority, application Yugoslavia, Aug. 3, 1967, 1,540/67 Int. Cl. C07c 47/18 U.S. Cl. 260-210 16 Claims ABSTRACT OF THE DISCLOSURE Monoand bis-carboxylic acid acylates of erythromycin oxime, useful as antibiotics.

The present invention relates to acyl derivatives of erythromycin oxime and to the preparation thereof.

It is known that acylation of erythrornycin with different acid chlorides or acid anhydrides yields a variety of products with a single acyl grouping attached to the hydroxyl group of the desosaminyl moiety. The sole exception is with the use of acetic anhydride as an acylating agent, which yield erythromycin diacetate. Some erythromycin esters, such as propionate, ethylsuccinate, ethylcarbonate, have been recommended in therapeutic practice owing to their advantages over erythromycin itself.

Since erythromycin oxime of the formula 3,574,185 Patented Apr. 6, 1971 TABLE I. ACYL DERIVATIVES OF ERYTHROMYCIN OXIME Acyl radical: Antibiotic activity U/rng. Mono-propionate 500-550 From the above table it can be seen that the acyl derivatives prepared by us with chlorides of aliphatic 5 and aromatic mono-carboylic acids, erythromycin oxime propionates are highly active. All acyl derivatives prepared with chlorides of aliphatic dicarboxylic acid esters possess well defined antibiotic activity.

The following example, in which the novel acyl derivatives of erythromycin oxirne are provided by the invention, is given by way of illustration:

possesses one additional group (oximino) which can be EXAMPLE 1 acylated it is possible to prepare monoand bis-acyl dflivatives thereof- Erythromycin oxime mono-propionate It has been found that monoand bis-acyl derivatives l be Prepare/{1 by the P of erythrolflycm 0X11 To a suspension of 5 g. (6.67 millimols) of erythrowith acid chlorides of aliphatic and aromatlc mono-carmycin oxime in 100 f dry acetone, 5 g. f dry boxyllc Qclds 0f the formula RCOCI Whereln R an sodium bicarbonate were added. Then, the solution of alkyl radlcal of 2 o 17 carbqn atglms or a phenyl radlcal, 0.790 g. (8.8 millimols) of propionyl chloride in 25 ml. with chlorides of dicarboxyhc ac1d esters of the formula f dry ace-tone was added dropwise with Stirring over a 2)n Wherem R 1S a10WeI alkyl radlcal period of one hour. After stirring for one additional t ethyl) and n 15 1 to m E Pmsfince of hour, the reaction mixture was filtered, the filtrate dialkali metal salt, such as sodium bicarbonate. If this luted with a solution of 2,5 Sodium bicarbonate in acylation is carried, out in inert anhyqwus Solvent 130 ml. Water and extracted with one 100 ml. and two Such as acetone using an eqlilvalent quantlty or a Small 50 ml. portions of ether. The combined ether extracts excess of the acylatmg agent In the presqnce of an alkah were dried over anhydrous sodium sulfate filtered and metal salt at room temperature, exclusively mono-acyl fie d fro 6th r in v c o For 31 derivatives can be obtained. With a slight excess over e d an ysl d two equivalents of the acylating agent in the presence of was pm 8 y PP m acemPe an a dmon O the double amount of an alkali metal salt in the $011k water pers stentturb1d1ty.A fter standingfor three hours, tion of same inert anhydrous solvent at elevated temperacrystanlsfitlon Set The Yleld was )1 ture, corresponding bis-acyl derivatives are formed.

The antibiotic activities of the obtained monoand Analysls--calculated for 4o 'z2 2 14 (P U C, bis-acyl derivatives, deter-mined on Bacillus subtilis and 59.63; H, 6.02; N, 3.48. Found (percent): C, 59.23; H,

Bacillus mycoides, are listed in Table I.

3 EXAMPLE 2 Erythromycin oxime mono-palmitate Erythromycin oxime mono-stearate From 5 g. (6.67 millimols) of erythromycin oxime, 2.616 g. (8.64 millimols) of stearoyl chloride and 2.5 g. of sodium bicarbonate, by the process described in Example 1, there are obtained 5.24 g. (77.49%) of mono-stearate, M.P. 74-78 C.

Analysis.-'Calculated for C H N O (percent): C, 65.05; H, 10.12; N, 2.76. Found (percent): C, 65.32; H, 10.33; N, 2.91.

EXAMPLE 4 Erythromycin oxime mono-benz oate From 5 g. (6.67 millimols) of erythromycin oxime, 1.26 g. (8.64 millimols) of benzoyl chloride and 2.5 g. of sodium carbonate, by the process described in Example 1, there are obtained 4.15 g. (73%) of monobenzoate, M.P. ISO-152 C.

Analysis.CalcuIated for C H N (percent): C, 61.95; H, 8.53; N, 3.28. Found (percent): C, 61.72; H, 8.28; N, 3.36.

EXAMPLE Erythromycin oxime mono-methylsuccinate- From 5 g. (6.67 millimols) of erythromycin oxime, 1.008 g. (6.67 millimols) of succinic methylester chloride and 2.5 g. of sodium bicarbonate, by the process described in Example 1, there are obtained 4.1 g. (70.9%) of monomethylsuccinate, M.P. 108-112 C.

Analysis-Calculated for C H N O (percent): C, 58.45; H, 8.76; N, 3.25. Found (percent): C, 58.60; H, 8.70; N, 3.54.

EXAMPLE 6 Erythromycin oxime mono-ethylsuccinate From 5 g. (6.67 millimols) of erythromycin oxime, 1.098 g. (6.67 millimols) of succinic acid ethylester chloride and 2.5 g. of sodium bicarbonate, by the process described in Example 1, there are obtained 4.23 g. (72.5%) of mono-ethylsuccinate, M.P. 99102. C.

Analysis.Calculated for C H N O (percent): C, 58.83; H, 8.74; N, 3.19. Found (percent): C, 58.57; H, 9.14; N, 3.38.

EXAMPLE 7 Erythromycin oxime mono-methyladipate From 5 g. (6.67 millimols) of erythromycin oxime, 1.19 g. (6.67 millimols) of adipic acid methylester chloride and 2.5 g. of sodium bicarbonate, by the process described in Example 1, there are obtained 4.5 g. (76%) of mono-methyladipate, M.P. 89-94 C.

Analysis.Calculated for C44H78N2O16 (percent): C, 59.30; H, 8.82; N, 3.14. Found (percent): C, 59.06; H, 8.60; N, 3.24.

EXAMPLE 8 Erythromycin oxime mono-ethyladipate From 5 g. (6.67 millimols) of erythromycin oxime, 1.28 g. (6.67 millimols) of adipic acid mono-ethylester chloride and 2.5 g. of sodium bicarbonate, by the process described in Example 1, there are obtained 4.8 g. (79.3%) of mono-ethyladipate, M.P. 82-86 C.

Arzalysis,-Calculated for C H N O (percent): C,

4 59.71; H, 8.91; N, 3.10. Found (percent): C, 59.52; H, 8.66; N, 3.01.

EXAMPLE 9 Erythromycin oxime bis-propionate To a suspension of 5 g. (6.67 millimols) of erythromycin oxime in ml. of dry acetone, 5.0 g. of dry sodium bicarbonate were added. Then the solution of 1.596 g. (17.29 millimols) of propionyl chloride in 50 ml. of dry acetone was added dropwise with stirring over a period of one hour. Stirring was continued for 8 hours more While heating the reaction mixture under reflux. After cooling to room temperature and filtration, the clear filtrate was diluted with a solution of 5 g. sodium bicarbonate in 250 ml. water and extracted with one 100 m1. and two 50 ml. portions of ether. The isolation of the product was performed in the same manner as described in Example 1. The yield was 4.49 g. (78.2%), M.P. 196-202 C.

Analysis.--Calculated for C H N O (percent): C, 59.97; H, 8.90; N, 3.25. Found (percent): C, 59.36; H,

EXAMPLE 1O Erythromycin oxime bis-palmitate From 5 g. (6.67 millimols) of erythromycin oxime, 4.5 g. (16.38 millimols) of palmitoyl chloride and 5 g. of sodium bicarbonate, by the process described in Example 9, there are obtained 6.31 g. (77%) of bis-palmitate, M.P. 6872 C.

Analysis.-Calculated for C H N O (percent): C, 67.71; H, 10.52; N, 2.29. Found (percent): C, 68.11; H, 10.41; N, 2.66.

EXAMPLE 11 Erythromycin oxime bis-stearate From 5 g. (6.67 millimols) of erythromycin oxime, 5 g. (16.52 millimols) of stearoyl chloride and 5 g. of sodium bicarbonate, by the process described in Example 9, there are obtained 6.2 g. (72.6%) of bis-stearate, M.P. 63.5-66.5 C.

Analysis.--Calculated for C73H136N2015 (percent): C, 68.40; H, 10.70; N, 2.18. Found (percent): C, 68.57; H, 10.55; N, 2.22.

EXAMPLE 12 Erythromycin oxime bis-benzoate From 5 g. (6.67 millimols) of erythromycin oxime, 2.52 g. (17.28 millimols) of benzoyl chloride and 5 g. of sodium bicarbonate, by the process described in Example 9, there are obtained 4.75 g. (74%) of bis-benzoate, M.P. 193-196" C.

Analysis.-Calculated for C51H76N2015 (percent): C, 64.00; H, 8.01; N, 2.92. Found (percent): C, 64.21; H, 8.19; N, 2.86.

EXAMPLE 13 Erythromycin oxime bis-methylsuccinate From 5 g. (6.67 millimols) of erythromycin oxime, 2.424 g. (16.1 millimols) of succinic acid methylester chloride, and 5 g. of sodium bicarbonate, by the process described in Example 9, there are obtained 5.18 g. (79.5%) of bis-methylsuccinate, M.P. 173176 C.

Analysis-Calculated for C H N O (percent): C, 57.74; H, 8.25; N, 2.86. Found (percent): C, 57.55; H, 8.55; N, 3.16.

EXAMPLE 14 Erythromycin oxime bis-ethylsuccinate From 5 g. (6.67 millimols) of erythromycin oxime, 2.649 g. (16.1 millimols) of succinic acid ethylester chloride and 5 g. of sodium in carbonate, by the process described in Example 9, there are obtained 4.92 g. (73.4%) of bis-ethylsuccinate, M.P. -162 C.

Analysis.Ca1culated for C H N O (percent): C, 58.54; H, 8.42; N, 2.78. Found (percent): C, 58.31; H, 8.20; N, 2.93.

EXAMPLE 15 Erythromycin oxime bis-methyladi'pate From g. (6.67 millirnols) of erythromycin oxime, 2.86 g. (16.1 millirnols) of adipic acid methylester chloride and 5 g. of sodium bicarbonate, by the process described in Example 9, there are obtained 5.25 g. (76.2%) of bis-methyladipate, M.P. 7883 C.

Analysis.Calculated for C H N O (percent): C, 59.28; H, 8.59; N, 2.71. Found (percent): C, 59.23; H, 8.83; N, 3.00.

EXAMPLE 16 Erythromycin oxime bis-ethyladipate From 5 g. (6.67 millirnols) of erythromycin oxime, 3.1 g. (16.1 millirnols) of adipic acid ethylester chloride and 5 g. of sodium bicarbonate, by the process described in Example 9, there are obtained 5.68 g. (80.1%) of hisethyiadipate, M.P. 72-76 C.

Analysis.Ca1cu1ated for C H N O (percent): C, 59.89; H, 8.17; N, 2.64. Found (percent): C. 60.25; H. 8.30; N, 2.90.

What We claim is:

1. Erythromycin oxime mono-propionate.

2. Erythromycin oxime mono-palmitate.

. Erythromycin oxime mono-stearate. Erythromycin oxime mono-benzoate. Erythromycin oxime mono-methy1succinate.

. Erythromycin oxime mono-methyladipate.

. Erythromycin oxime mono-ethyladipate.

3 4 5 6. Erythromycin oxime mono-ethylsuccinate. 7 8 9 References Cited UNITED STATES PATENTS 12/1958 Booth et a1. 260--210E 1/1961 Clark, J1. 260210E 7/ 1961 Stephens 26021'0E 12/1961 Druey et a1. 260-211 LEWIS GOTTS, Primary Examiner 25 I. R. BROWN, Assistant Examiner US. Cl. X.R.

P040510 UNITED STATES PATENT OF ?ICE 56 CERTIFICATE OF CORR ECTION Pat Lent No. 3 ,57 H 5 Dated April 6, 1971 lnventofls) Zrinka 'Iamburasev, GabriJela S. Vazdar-Kobrehel W 0 an JOklc It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 2, line 60: before "persistent" insert --until--.

001. line 73: correct "sodium in carboinate" to read --sod1um b1oarbonate--.

Signed and sealed this 13th day or July 1971.

(SEAL) Atteat:

EDWARD M.FLETGHEH,JH. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

